Both active and passive immunotherapies have shown increasing promise as treatments for human B cell lymphomas. A fundamental feature of the biology of these diseases that may influence the response to inununotherapy is the fact that lymphoma cells are the transformed counterpart of key components of the immune system itself. For example, as a tumor derived from antigen presenting cells (APCs), B cell lymphomas are well equipped to process antigen and engage in cognate interactions with lymphoma antigen- specific T cells. Consequently, therapeutic strategies seeking to manipulate anti-tumor immunity will effect both the normal host response to lymphoma antigens as well as the tumor directly. In this proposal, we seek to understand and exploit this aspect of lymphoma biology in our efforts to develop effective immunotherpies for B cell lymphoma. These projects will utilize well-characterized murine models for the purpose of comparing therapeutic efficacy of several vaccine and antibody based therapies, and identifying their underlying mechanism of action. Those strategies showing the greatest promise in preclinical models will be directly evaluated in early phase clinical trials. Specifically, we will: 1) Seek to enhance the efficacy of GM-CSF tumor cell-based vaccination through the use of a universal GM-CSF producing bystander cell engineered to co-express tumor necrosis factor (TNF)/TNF receptor family members. Vaccination with irradiated autologous lymphoma cells mixed with such a bystander cell line will be compared to our current vaccine formulation (tumor + GM-CSF bystander alone). The influence of TNF/TNFr family member signaling on host APCs recruited to the vaccine site versus on the vaccinating lymphoma cells will be compared. 2) Evaluate systemic treatment with monoclonal antibodies (mAb) targeting CD40, OX40, and CTLA-4 as single agents and in combination with tumor cell-based vaccines. The influence of each of these on the function of host immunity (e.g. A-PC activation, and enhanced T cell priming respectively) will be compared to direct effects on lymphoma cells in vivo. 3) Explore antibody therapy and tumor vaccines for the treatment of lymphoma during immune reconstitution following autologous (or in the mouse, syngeneic), hematopoietic stem cell transplantation (HSCT). In addition to these in vivo therapies, we will seek to augment the anti-lymphoma immune response through the ex vivo manipulation of autologous lymphocytes that accompany the graft during transplantation.
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